N2-(N,N-dimethyl-L-valyl)-N-[(1S,2R)-2-methoxy-4-[(2S)-2-[(1R,2R)-1-methoxy-2-methyl-3-oxo-3-[(2-phenylethyl)amino]propyl]-1-pyrrolidinyl]-1-[(S)-1-methylpropyl]-4-oxobutyl]-N-methyl-L-valinamide [TZT-1027] represented by the following formula (I)
is a tetrapeptide derivative possessing potent antitumor activity, and is a potential anti-cancer agent.
TZT-1027 per se has been disclosed in, for example, PCT International Publication WO93/03054 Pamphlet, which describes purification of crude TZT-1027 with preparative thin-layer chromatography and column chromatography, to provide amorphous TZT-1027 powder. Chem. Pharm. Bull., 43(10), 1706-1718 (1995) also describes purification of crude product first by means of flash chromatography or preparative thin-layer chromatography and then column chromatography to provide TZT-1027 as an amorphous powder. JP Hei 7 (1995)-2894A, furthermore, discloses TZT-1027, in which again crude TZT-1027 was purified by column chromatography and preparative thin-layer chromatography to provide a fluffy solid TZT-1027.
As above, amorphous TZT-1027 has been reported in the past, but no literature disclosing crystalline TZT-1027 is found.
Generally speaking, compounds in amorphous form require more complicated purification operations than those in crystalline form do, and frequently their stability is insufficient. In particular, where the compounds are used as active ingredients of pharmaceutical compositions, their insufficient purity can provide problems. In also formulation operations, where the compounds are in amorphous form, amorphous powder is apt to be blown up and require more cautious handling than cases of formulating crystalline compounds. For these reasons, in using TZT-1027 having potent antitumor activity as an active ingredient of pharmaceutical compositions, crystalline TZT-1027 is considered preferable compared to known amorphous form.
We have made various attempts to crystallize TZT-1027, but its crystallization was very difficult because it is a peptide compound. For instance, TZT-1027 crystals could not be obtained through crystallization using such solvents as alcohols, halogenated hydrocarbons, nitrites, ketones, organic acids, water and the like. We furthermore tried the crystallization using ethers such as diisopropyl ether, tetrahydrofuran and the like, or hydrocarbons such as n-pentane, n-hexane, cyclohexane and the like without success.